Methods
Eligibility criteria included clinically definite Multiple Sclerosis, Expanded Disability Status Scale score 0 to 5.0, no previous use of GA, at least one relapse in the previous year, and 1 to 15 Gadolinium-enhancing (GdE) lesions on a screening MRI.

MRI was repeated at months 3, 7, 8, and 9, and neurologic examinations were performed at baseline and months 3, 6, and 9.

The primary efficacy endpoint, total number of GdE lesions at months 7, 8, and 9, showed a trend favoring the 40-mg group (38% relative reduction, p = 0.0898).

A difference between the two dose groups emerged as early as month 3 (52% reduction; p = 0.0051).

There was a trend favoring the 40-mg group for relapse rate with benefit on proportion of relapse-free subjects (p = 0.0183) and time to first relapse (p = 0.0367).

GA 40 mg was well tolerated, with an overall safety profile similar to that of 20 mg. Some features of injection site reactions and immediate postinjection reactions were more common and severe with the higher dose.

The Corpus Callosum Area (CCA) in a midsagittal image is age independent in a normal adult population up to the seventh decade; therefore it can be used as a marker for non-age-related, pathological Brain Atrophy.

Objectives
To investigate whether and how CCA decreases in size over time in patients with MS.

Methods
In a clinical observational study, 37 patients with MS with a wide range of disease duration at baseline (1-33 years) were followed. Three different MS courses were represented.

The mean of individual MRI follow-up was 9 years. Multiple Sclerosis Severity Score (MSSS) was also applied to evaluate disability at baseline and after 9 years of follow-up.

Results
A significant decrease in CCA over 9 years (p < 0.001) and a persisting association between CCA and the disability status were found.

The Atrophy rate was similar over four decades of MS for all MS courses. The mean annual CCA decrease was 9.25 mm2 (1.8%). Surprisingly, Atrophy rate did not correlate with sex, disease duration, age at MS onset or MS course.

Conclusions
Serial evaluations of CCA might be a robust method in monitoring a non-age-related decrease in CCA, reflecting progression of irreversible destructive changes in MS.

Objective
To study the effect of Testosterone supplementation on men with Multiple Sclerosis (MS).

Design, Setting, And Participants
Men are less susceptible to many Autoimmune Diseases, including MS. Possible causes for this include sex hormones and/or sex chromosome effects.

Testosterone treatment ameliorates Experimental Allergic Encephalomyelitis, an animal model of MS, but the effect of Testosterone supplementation on men with MS is not known.

Therefore, 10 men with Relapsing/Remitting MS were studied using a crossover design whereby each patient served as his own control. There was a 6-month pretreatment period followed by a 12-month period of daily treatment with 10 g of the gel containing 100 mg of Testosterone.

Purpose Of Review
The aim of this review is to summarize the current literature on the NeuroPsychiatry of Multiple Sclerosis (MS).

Recent Findings
Data from community samples have supported earlier findings from tertiary referral centres of high rates of Depression in MS patients.

NeuroImaging offers important clues as to the pathogenesis of Depression, but PsychoSocial factors cannot be ignored and emerge as equally important predictors.

Cognitive-behavioural therapy is an effective treatment, rivalling standard dosing of Sertraline in patients with Depression.

An allied disorder - Pseudobulbar Affect - occurs in up to 10% of MS patients and responds well to a combination of Dextromethorphan and Quinidine. Cognitive Dysfunction affects approximately 40% of MS patients.

Moreover, functional MRI studies have demonstrated the Brain's ability to compensate, in part, for damage. Should the disease burden be too severe, however, compensatory mechanisms fail and Cognitive deficits increase accordingly.

Summary
NeuroPsychiatric abnormalities are common in MS patients. No aspect of mentation is spared. Advances in NeuroImaging are increasing our understanding of the pathogenesis of these disorders.

Translating these findings into improved methods of treatment for patients presents researchers with pressing challenges.

Background
Although Cognitive Impairment is common in patients with Multiple Sclerosis (MS), its value as a clinical trial endpoint remains uncertain.

For example, in the randomized, blinded, pivotal trial of Glatiramer Acetate (GA) in patients with Relapsing MS, improvements occurred in NeuroPsychological test scores during 2 years of treatment regardless of whether patients received GA or placebo, likely due to practice effects.

Objectives
To assess long-term changes in NeuroPsychological status following 10 years of prospective evaluation in a typical ImmunoTherapy trial cohort.

Methods
Participants in the ongoing open-label GA extension study repeated the Brief Repeatable Battery of NeuroPsychological Tests an average of 10.6+/-0.4 years after their initial baseline evaluation.

Results
Mean scores on tests of memory and semantic retrieval were not significantly changed over 10 years of follow-up, but tests of Attention showed declines for the group as a whole.

Using a threshold of a 0.5 SD decline to define significant worsening, individual tests showed declines in 27-49% of participants and a composite score showed worsening in 19%.

Fatigue is one of the most common and most disabling symptoms of Multiple Sclerosis (MS). Although numerous studies have tried to reveal it, no definite pathogenesis factor behind this Fatigue has been identified.

Fatigue may be secondary to sleep problems, which are frequently present in MS and in their turn result from Urinary problems, Spasms, Pain, or Anxiety. Pharmacologic treatment of MS (symptoms) may also provoke Fatigue.

The evidence for reduced activity as a cause of secondary Fatigue in MS is inconsistent. Psychological functioning may at least play a role in the persistence of Fatigue.

Research did not reach consensus about the association of Fatigue with clinical or demographic variables, such as age, gender, disability, type of MS, education level, and disease duration.

In conclusion, it is more likely to explain Fatigue from a multifactor perspective than to ascribe it to one mechanism.

The current evidence on the pathogenesis of primary and secondary Fatigue in MS is limited by inconsistency in defining specific aspects of the concept Fatigue.

By the lack of appropriate assessment tools, and by the use of heterogeneous samples. Future research should overcome these limitations and also include longitudinal designs.

No differences were observed between OND (median: 0.57 IQR: 0.28-0.73) and MS patients.

Conclusions
CSF NAA concentration in MS patients is related to clinical performance and MRI measures of disease burden and may therefore be an important Neuron specific marker of disease severity and possibly progression.

#10

Progression In Multiple Sclerosis: Further Evidence Of An Age Dependent Process

The Relapsing/Remitting phase and the Progressive phase of Multiple Sclerosis (MS) seem to be the result of distinct pathophysiological processes.

Previous research on the natural history of MS was largely focussed on relapses and disability scores. In this study we evaluated 438 patients with Secondary or Primary/Progressive MS.

The influence of gender, initial disease course, onset manifestation and age at disease onset on age at progression and time to progression were evaluated with Kaplan-Meier survival analysis and Cox multivariate regression models.

The analysis of these data showed that the initial disease course (SPMS or PPMS) had no influence on the age at progression.

Gender had no influence on age at progression in PPMS and SPMS patients nor on time to progression in SPMS patients.

PPMS patients with Visual or BrainStem/Cerebellar onset had a significantly younger age at progression.

SPMS patients with Motor onset had a significantly higher age at progression and longer time to progression.

Time to progression was significantly shorter in SPMS patients with higher age at disease onset.

Our data give further support to the notion that progression in MS is an age dependent process independent of relapses.

Therapy with Interferon-beta (IFN-ß) has well-established clinical effects in Multiple Sclerosis (MS), albeit the ImmunoModulatory mechanisms are not fully understood.

We assessed the prevalence and functional capacity of CD4+ and CD8+ T-Cells in healthy donors, and in untreated and IFN-ß-treated MS patients, in response to Myelin Oligodendrocyte Glycoprotein (MOG).

The proportion of CD45RO+Memory T-Cells was higher in MS patients than in healthy donors, but returned to normal values upon therapy with IFN-ß.

While CD45RO+CD4+ T-Cells from all three groups responded to MOG in vitro, untreated patients showed augmented proliferative responses compared to healthy individuals and IFN-ß treatment reduced this elevated reactivity back to the values observed in healthy donors.

Similarly, the response of CD45RO+CD8+ T-Cells to MOG was strongest in untreated patients and decreased to normal values upon ImmunoTherapy.

Overall, the frequency of peripheral CD45RO+Memory T-Cells ex vivo correlated with the strength of the cellular in vitro response to MOG in untreated patients but not in healthy donors or IFN-ß-treated patients.

Natalizumab is a new treatment option for patients with active Relapsing/Remitting Multiple Sclerosis.

In phase III studies, Natalizumab was highly effective and well tolerated; however, three cases of Progressive Multifocal Leucoencephalopathy (PML) were identified (estimated incidence of one per 1000; 95% CI 0.2-2.8; mean treatment period 17.9 months).

In this Review we summarise the current information on PML, the three confirmed cases of PML, and the results of an extensive safety assessment of all patients treated with Natalizumab.

On the basis of these reviews, we make recommendations for appropriate selection of candidates for Natalizumab and pretreatment assessments.

In addition, a three-step diagnostic and management algorithm was developed to monitor Natalizumab-treated patients with Multiple Sclerosis for PML and other opportunistic infections. The algorithm includes strategies for clinical, MRI, and laboratory assessments.

Maintaining clinical vigilance allows for early suspension of Natalizumab in potential cases of PML, thereby increasing the opportunity for Immune reconstitution, which may improve prognosis if PML is confirmed